Symposium: Between a Rock and a Hard Place: Dietary

and Toxicological Standards for Essential Minerals

Dietary Standards for Manganese: Overlap between Nutritional and

Toxicological Studies1,2
J. L. Greger
Department of Nutritional Sciences, University of Wisconsin, Madison, WI 53706

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ABSTRACT The Estimated Safe and Adequate Daily Dietary Intake (ESADDI) for adults for manganese is 2–5
mg Mn/d. The LOAEL (lowest-observable-adverse-effect level) for manganese in water is 0.06 mg Mn/(kgrd) or
4.2 mg Mn/d for a 70-kg individual. The inconsistency in these standards reflects limitations in the available data
as well as differences in the way in which the standards are calculated. Manganese balance and excretion data
are not useful biomarkers of manganese exposure but do demonstrate that the body is protected against manga-
nese toxicity primarily by low absorption and/or rapid presystemic elimination of manganese by the liver. Serum
manganese concentrations in combination with lymphocyte manganese-dependent superoxide dismutase
(MnSOD) activity, and perhaps blood arginase activity, seem to be the best way to monitor ingestion of insufficient
manganese. Serum manganese concentrations in combination with brain magnetic resonance imaging (MRI)
scans, and perhaps a battery of neurofunctional tests, seem to be the best way to monitor excessive exposure
to manganese. J. Nutr. 128: 368S–371S, 1998.

KEY WORDS: • manganese • toxicity • manganese-dependent superoxide dismutase

• magnetic resonance imaging (MRI) • arginase

In the past, the establishment of nutritional and toxicologi-
cal standards for minerals has not been coordinated. This has
led to inconsistencies between the nutritional standards [e.g.,
the Recommended Dietary Allowance (RDA)3 and Estimated
Safe and Adequate Daily Dietary Intake (ESADDI)] and the
toxicological standards [e.g., the reference dose (RfD) and low-
est-observable-adverse-effect level (LOAEL)].
In 1989, the Food and Nutrition Board, in the absence of
good biomarkers (indicators of nutritional or toxicological sta-
tus in regard to manganese), based the ESADDI for manganese
on typical intakes of manganese and on data from short-term
balance studies (NRC 1989). Similarly the Environmental
Protection Agency (EPA) used estimates of manganese levels
in typical Western and vegetarian diets to calculate the RfD
for manganese in food (Velazquez and Du 1994). Thus the
1
Presented as part of the symposium ‘‘Between a Rock and a Hard Place:
Dietary and Toxicological Standards for Essential Minerals’’ given at the Experi-
mental Biology 97 meeting, April 7, 1997, New Orleans, LA. This symposium was
sponsored by the American Society for Nutritional Sciences (ASNS), the ASNS
Research Interest Sections on Vitamins and Minerals and Nutrient and Food
Toxicology. The symposium was supported in part by educational grants from
the United States Department of Agriculture, Agricultural Research Service and
the National Cattlemen’s Beef Association. Guest editors for the symposium pub-
lication were Suzanne Hendrich, Food Science and Human Nutrition, Iowa State
University, and Janet L. Greger, Department of Nutritional Sciences, University
of Wisconsin, Madison.
2
Supported by the College of Agricultural and Life Sciences, University of
Wisconsin-Madiosn project number 2623 and the Graduate School.
3
Abbreviations used: EPA, Environmental Protection Agency; ESADDI, esti-
mated safe and adequate daily dietary intake; LOAEL, lowest-observable-ad-
verse-effect level; MnSOD, manganese-dependent superoxide dismutase; MRI,
magnetic resonance imaging; RDA, recommended dietary allowances; RfD, refer-
ence dose; TPN, total parenteral nutrition.
ESSADDI is 2–5 mg Mn/d and the RfD for manganese in food
is 0.14 mg Mn/(kgrd) or 10 mg Mn/d for a 70-kg individual.
EPA officials thought that a separate standard was required
for manganese in drinking water because of the potentially
greater bioavailability of manganese in water than in food
(Velazquez and Du 1994). Data from an epidemiological study
by Kondakis et al. (1989) were used. Kondakis et al. (1989)
observed more neurological symptoms among individuals
ú 50 y of age living in areas in Greece in which the drinking
water contained 1.8–2.3 mg Mn/L than among individuals
living in areas in which the drinking water contained õ0.015
mg Mn/L. Assuming that a 70-kg individual would consume
2 L of water daily, the EPA estimated the LOAEL for manga-
nese in water to be 4.2 mg Mn/d or 0.06 mg Mn/(kgrd) (Velaz-
quez and Du 1994).
Thus these standards ‘‘suggest’’ on the basis of very limited
data that individuals consuming the amount of manganese
recommended by the ESADDI (5 mg Mn/d) could consume
‘‘excessive’’ amounts of manganese (ú4.2 mg Mn/d) if much
of the manganese came from water. Conflicting standards of
this sort lead to either alarm and/or cynicism among the public
and scientists. Obviously, policy decisions such as toxic clean-
up efforts and food fortification should be based on stronger
scientific evidence.
The rest of this review will examine the types of data that
are available for use in calculating nutritional or toxicological
standards. The limitations of the data will be noted.
MANGANESE EXPOSURE
One reason for the difficulty in recommending optimal in-
takes of manganese is that scientists really are not sure of

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 MANGANESE: NUTRITION AND TOXICOLOGY
typical manganese intakes. Daily food composites prepared on
the basis of the FDA’s Total Diet Study menus contained
on average 2.2 mg Mn for women and 2.7 mg Mn for men
(Pennington et al. 1989). The average intakes of adults eating
Western-type and vegetarian diets in various surveys ranged
from 0.7 to 10.9 mg Mn/d (Freeland-Graves 1994, Gibson
1994).
These variations in manganese intakes reflect variations in
food choices. Pennington and Young (1991) calculated that
grain products contributed 37%, beverages (particularly tea)
contributed 20% and vegetables contributed 18% of the man-
ganese in the FDA’s Total Diet Study menu for 30- to 35-y-
old males.
BIOMARKERS FOR MANGANESE EXPOSURE
Another limitation faced by experts trying to establish nu-
tritional and toxicological standards for manganese is that the
levels of oral intake of manganese associated with adverse
effects (both deficient and toxic) are debatable. This reflects
the scarcity of specific biomarkers for manganese.
Manganese balance and excretion. In general, data from
balance studies do not provide useful biomarkers of manganese
exposure. Manganese balances during short- and moderate-
term balance studies do not appear to be proportional to man-
ganese intakes. Subjects in carefully controlled studies
achieved positive balances in regard to manganese when fed
diets containing 2.55–15.0 mg Mn/d (Freeland-Graves et al.
1988, Friedman et al. 1987, Greger et al. 1978b, Schwartz et al.
1986) and achieved negative balances in regard to manganese
when fed diets containing 0.011–13.9 mg Mn/d (Freeland-
Graves et al. 1988, Friedman et al. 1987, Greger et al. 1978a,
Greger and Baier 1983, Schwartz et al. 1986).
The wide range of manganese intakes at which positive
manganese balances were achieved reflects a number of factors.
Past manganese intakes of subjects and contents of iron, cal-
cium, phosphorus and phytate in the diet have all been found
to affect manganese retention (Davis et al. 1992, Freeland-
Graves 1994, Keen and Zidenberg-Cherr 1996, Lee and John-
son 1988, Schwartz et al. 1986, Wedekind et al. 1991).
Moreover, traditional balance techniques are inadequate for
assessing manganese absorption because absorbed manganese is
very quickly (within minutes) secreted into the gut as bile
(Davidsson et al. 1989, Davis et al. 1993b, Lee and Johnson
1988). Hence separation of unabsorbed manganese from en-
dogenous gut losses of manganese is difficult. However, Da-
vidsson et al. (1989), on the basis of Mn-54 retention from
meals, estimated that adult humans absorbed 5.9 { 4.8%
(mean { SD) of ingested manganese. Davis et al. (1993b)
estimated that growing rats absorbed 8.7% of their manganese
intake but lost 37% of the absorbed manganese through gut
secretions, presumably bile.
Accordingly, biliary manganese secretion might be a bio-
marker of deficient or excessive intake of manganese. However,
biliary manganese excretion was found to be roughly propor-
tional to recent injected or oral doses of aluminum but not to
body stores of manganese (Malecki et al. 1996, Thompson and
Klaassen 1982).
The usefulness of urinary manganese as an indicator of oral
manganese exposure is also doubtful. Friedman et al. (1987)
showed that urinary manganese excretion by men tended to
decline during severe manganese depletion and to increase
during repletion. However, Davis and Greger (1992) could not
demonstrate that women given 15 mg Mn/d during a 125-d
supplementation trial excreted more manganese in urine than
women consuming 1.7 mg Mn/d in food.
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FIGURE 1 Changes in serum manganese concentrations in 47
women supplemented with 15 mg Mn/d (h), 60 mg Fe/d (s), 15 mg
Mn and 60 mg Fe (m), or placebo (j). Values are mean { SEM. *P
õ 0.05; †P õ 0.01; and §P õ 0.0001 compared with placebo at the
same time point. Reprinted with permission from Davis and Greger
(1992).
In general, the balance data demonstrate that the body is
protected against manganese toxicity primarily by low absorp-
tion and/or rapid presystemic elimination of manganese by the
liver. Accordingly, the potential of excess accumulation of
manganese and toxic symptoms would be greater when manga-
nese is delivered parenterally vs. orally or when liver function
and biliary secretion are decreased.
Tissue manganese concentrations. The biomarkers most
used for manganese exposure in animal studies are tissue man-
ganese concentrations (Brock et al. 1994, Davis et al. 1990,
DeRosa et al. 1980, Hurley and Keen 1989, Keen and Ziden-
berg-Cherr 1996, Malecki and Greger 1995, Malecki et al.
1996, Paynter 1980). Malecki et al. (1994) noted a fairly uni-
form loss of 40–50% of the manganese in tissues of rats fed
Ç1 mg Mn/g diet for 2 mo.
Unfortunately, most tissues are inaccessible in humans
without biopsies. Serum manganese is the most easily available
biomarker of manganese status in humans. Davis and Greger
(1992) found that women consuming 1.7 mg Mn/d had lower
serum manganese concentrations than women ingesting 15 mg
of supplemental manganese for more than 20 d (Fig. 1).
Hambidge et al. (1989) reported that plasma manganese
levels were elevated in infants with choleostatic liver disease
who were given supplemental manganese in total parental
nutrition (TPN) solutions. Similarly, others have observed
manganese accumulation in blood, brain and liver of patients
provided with supplemental manganese in parenteral solutions
(Fell et al. 1996, Mehta and Reilly 1990, Mirowitz and West-
rich 1992, Ono et al. 1995) and in patients with impaired
liver function or biliary secretion (Fell et al. 1996, Hauser et
al. 1994, Mehta and Reilly 1990, Versieck et al. 1974).
Symptoms of manganese deficiency. Most of the gross
symptoms (e.g., growth retardation, dermatitis or reproductive
failure) and metabolic changes (e.g., reduced HDL cholesterol
levels or diabetic-like glucose tolerance curves) observed in
severely manganese-deficient animals are not specific enough
to use as biomarkers (Baly et al. 1990, Davis et al. 1990,
Friedman et al. 1987, Keen and Zidenberg-Cherr 1996, Taylor
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370S SUPPLEMENT
et al. 1996). The exceptions are the gross skeletal changes that
occur during manganese deficiency. They are characterized by
enlarged joints, deformed legs with thickened and shortened
long bones and lameness in pigs, ruminants and poultry (Hur-
ley and Keen 1989).
Symptoms of manganese excess. Typical symptoms (i.e.,
depressed appetite, growth depression, reproductive failure and
anemia) of chronic oral exposure to excess manganese are
nonspecific (Hurley and Keen 1989). The consequences of
chronic inhalation of excess manganese, as occurs among man-
ganese miners, are more specific and include a severe psychiat-
ric disorder resembling schizophrenia and an irreversible neu-
rological disorder resembling Parkinson’s disease (Hurley and
Keen 1989).
Biomarkers that can indicate excessive manganese exposure
before permanent neurological symptoms appear must be iden-
tified. Neurological tests have been used in at least two epide-
miological studies to gauge the toxicity of manganese in water
(Kondakis et al. 1989, Vieregge et al. 1995). Other investiga-
tors have reported that altered responses to a battery of neuro-
functional tests (e.g., postural instability when visual input is
prevented, slowed finger tapping speed, increased reaction
times or decreased hand steadiness) were useful in identifying
excess manganese exposure among industrial workers who were
still asymptomatic for the classic neurological symptoms of
manganese toxicity (Chia et al. 1995, Iregren 1994, Mergler
et al. 1994). The results of neurofunctional tests and biological
indications of excess manganese exposure should be studied
together in the future to assess their relative usefulness.
Magnetic resonance imaging (MRI) scans of brains may
provide useful biomarkers for excess exposure to manganese.
High intensity signals of several regions of the brain, but espe-
cially the globus pallidus, have been observed in T-1 weighted
MRI scans of patients receiving manganese-supplemented
TPN solutions (Fell et al. 1996, Mirowitz and Westrich 1992,
Ono et al. 1995) and/or scans of patients who have compro-
mised liver or biliary function (Fell et al. 1996, Hauser et al.
1994). The abnormal imaging was reduced after manganese
was removed from the TPN solutions in at least two cases
(Mirowitz and Westrich 1992, Ono et al. 1995). Nelson et al.
(1993) observed similar high intensity signals from the globus
pallidus of the brain of a man who had been an arc welder for
25 y.
Activity of manganese-activated enzymes and metalloen-
zymes. Scientists have had difficulty identifying enzymes that
could be useful biomarkers for several reasons. Many of the
manganese-activated enzymes are activated by other ions, es-
pecially magnesium (Keen and Zidenberg-Cherr 1996). Most
manganese-activated enzymes are not reduced during manga-
nese deficiency. The exceptions are phosphoenol pyruvate car-
boxykinase and the glycosyltransferases and xylosyltransfer-
ases, which are important in proteoglycan synthesis during
bone formation (Baley et al. 1985, Hurley and Keen 1989).
There are three primary manganese metalloenzymes. The
activity of one, liver pyruvate carboxylase, is more sensitive
to developmental changes than to manganese intake (Baly et
al. 1985). The activity of the second, arginase, is depressed in
livers of manganese-deficient rats (Paynter 1980). Moreover,
manganese-deficient rats had not only depressed hepatic argi-
nase activity but also depressed plasma urea and elevated
plasma ammonia concentrations (Brock et al. 1994). Unfortu-
nately, the usefulness of arginase as a biomarker in clinical
situations is debatable because a variety of factors, including
diabetes, liver disease and ingestion of high protein diets, can
affect arginase activity (Morris 1992).
The third manganese metalloenzyme is mitochondrial or
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FIGURE 2 Changes in lymphocyte manganese-dependent super-
oxide dismutase (MnSOD) activity in 47 women supplemented with 15
mg Mn/d (h), 60 mg Fe/d (s), 15 mg Mn and 60 mg Fe (m), or placebo
(j). Values are means { SEM. *P õ 0.05 and †P õ 0.01 compared
with placebo at the same time point. Reprinted with permission from
Davis and Greger (1992).
manganese-dependent superoxide dismutase (MnSOD).
MnSOD activity is usually depressed in heart and often de-
pressed in the livers of manganese-deficient animals (Davis et
al. 1990 and 1992, DeRosa et al. 1980, Malecki et al. 1994,
Malecki and Greger 1995, Zidenberg-Cherr et al. 1983).
However, little work had been done to assess MnSOD activ-
ity in humans. Davis and Greger (1992) demonstrated that
lymphocyte MnSOD activity was elevated in women ingesting
15 mg of supplemental Mn/d for ú90 d (Fig. 2). Unfortu-
nately, MnSOD is not a perfect biomarker. MnSOD activity
can also be affected by a variety of factors that induce oxidative
stress, including ethanol (Keen et al. 1985), diets rich in poly-
unsaturated fatty acids (Davis et al. 1990, Phylactos et al.
1994), non-heme iron (Davis et al. 1993a) and strenuous phys-
ical exercise (Ohno et al. 1993).
The reduction of MnSOD activity in manganese deficiency
is interesting because it can be related to symptoms. Malecki
and Greger (1996) observed that manganese-deficient rats had
more oxidative damage (as indicated by increased conjugated
diene formation) in the mitochondrial membranes of their
hearts than did control rats. The conjugated diene levels were
inversely correlated (r Å 00.71, P õ 0.005) to MnSOD activ-
ity in the heart.
SUMMARY
There are no perfect biomarkers for assessing manganese
exposure. However, serum manganese concentrations in com-
bination with lymphocyte MnSOD activity and perhaps blood
arginase activity seem to be the best way to monitor ingestion
of insufficient manganese intake. Serum manganese concentra-
tions in combination with brain MRI scans and perhaps a
battery of neurofunctional tests seem to be to the best ways
to monitor excessive exposure to manganese. A combination
of these biomarkers should be used to estimate standards such
as the ESSADI and RfD for manganese.
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 MANGANESE: NUTRITION AND TOXICOLOGY
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